Breath-Based Volatile Metabolite Panel for Early Diagnosis and Precision Management of Acute Lung Injury/ARDS in Critical Care

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are major causes of morbidity and mortality in intensive care, yet current Berlin criteria lack molecular specificity and offer little support for early, individualized management. This study applied untargeted gas chromatography–mass spectrometry (GC–MS) metabolomics of exhaled breath condensate to identify volatile organic compound (VOC) signatures associated with ALI/ARDS. Twenty five participants (12 ALI patients, 13 healthy controls) were enrolled. Global metabolic profiles were evaluated using covariate adjusted linear models, principal component analysis, and orthogonal partial least squares discriminant analysis, with diagnostic performance assessed by receiver operating characteristic curves. A stringent multi-step selection strategy yielded five high-confidence metabolites that clearly distinguished ALI/ARDS patients from controls, each showing excellent diagnostic accuracy with area under the curve values above 0.90, including several at 1.00. Temporal analysis between ICU Day 0 and Day 1 revealed limited global shifts, suggesting that early ALI is driven by metabolite-specific disturbances rather than broad changes in pathways. Biological interpretation implicated a cytochrome P450–related oxidative imbalance, disruption of the heme oxygenase-1/protoporphyrin IX redox axis, and short-chain fatty acid–linked gut–lung dysfunction, alongside two novel but uncharacterized markers of tissue stress. These findings indicate that GC-MS-based breathomics can non‑invasively capture clinically relevant metabolic alterations in ALI/ARDS and support development of VOC panels for early diagnosis, risk stratification, and precision management in critical care.